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Wednesday, January 11, 2012

Do we still not know what causes cancer? Part II

Part I in this series described the SMT, or somatic mutation theory of cancer. The original theory was developed from some data on both the epidemiology and the known cases of inheritance of cancer susceptibility. It lead to a focus on the idea that, at the cell level, cancer was a misbehavior disorder due to mutations--changes in DNA--in genes whose normal function was critical for the cell type in question--be it lung cells, intestinal cells, or other tissues. The cell can't behave properly if its relevant genes have been changed. The idea is then that a given case of cancer is due to the spread of a clone of cells, descended in the person's body from a single initial 'transformed'--misbehaving--cell, and cells in that clone then accumulate a diversity of subsequent mutations.

Tests of clonality and searches for mutations have been done, and these have been successful. Similarly, genomewide tests have shown that cancer cells, relative to host normal cells, do reflect many mutational differences. At least some of these are repeatedly found, and are in genes related to cell division and other relevant aspects of behavior. Some of these changes can be inherited, leading to elevated risk, as we described briefly in Part I. The picture was complex--essentially, polygenic, with different tumors manifesting different mutations. Still, patterns of mutational change have been shown to be relevant to response to therapy and prognosis. It all seemed consistent with the SMT.

However, there were some weak points in the data. Normal cells also show mutations, and cataloging the differences from tumor cells is difficult. After all, even under the SMT, normal cells would be expected to show mutations in the same genes found changed in tumors, because that's how the combinations of 'bad' changes accumulate.

Further, a 'theory' of the essential qualities of life, that goes beyond our contemporary obsession with Darwinian selection and genetic determinism based on competition, such as we try to discuss in MT (here, and in our book of the same name), stresses the role of complex multi-component cooperation in the nature of life among organisms, species, and cells. Signaling interactions are a fundamental property of that cooperative aspect of life. A cell's behavior is instructed by its current constituents (including the genes it's using at the time) and the conditions it detects in its environment. What it detects alters the genes it will express or repress. A stomach cell expresses appropriate genes for stomach-related behavior, but not genes involved in, say, liver, brain, or blood. When the environment changes, the cell changes its gene expression and its behavior (thus, when a stomach stem cell detects the absence of adjacent differentiated stomach cells, it divides to replace the lost cells.

What we know about such complex phenomena is that they typically are polygenic, that is, are affected by many genes, and their variation can be due to many different combinations of variation in those genes. This is what we write a lot about, for example, in the context of GWAS findings. In our view, to this extent, cancer like other complex traits, is a polygenic phenotype involving cell-to-cell signaling as a determinant of the complex structure of organs like lungs, skin, brains, and ovaries.

Thus, a key feature of life is properly timed preparation, detection, and responsiveness of cells. Once it becomes committed to the environment it has been prepared to detect, or to whose changes it detects, it is channeled in particular directions....and its set of expressed response detectors (signal receptors, for example) limit what it can do in the future. In a polygenic view of tissue behavior, there would be many different ways to go awry.

Viruses and other cellular components, normal and from the outside, can also enter the genome or pop copies of themselves elsewhere in the genome. This can lead to abnormal effects on the regular genes in the vicinity of the genome where such a copy has, by chance, landed. For example, a gene may be induced to be expressed abnormally as the result of such events. This is not a mutation in the expressed gene itself, but in its anomalous usage. But once the transposed bit of DNA is there, the cell and its descendants are doomed to obey its effects! It is, in a sense, a kind of somatic mutation, but would never be detected in sequencing the affected gene itself.

The May 2011 BioEssays point-counterpoint includes one part, by Vaux, defending the SMT, but opposed by Soto and Sonnenschein who argue for a tissue organization field theory (TOFT). One need not accept all-or-nothing combative 'theories' to ask whether we have somehow misinterpreted the SMT, leading to a research focus that will have only limited success, if based on the expectation of mutant genes as the cause of cancer. That can be important, of course, in the research approach to effective therapies. But it could also be important in what we understand about genetics....and even about evolution and life itself. That's because we might have been too deterministic in assuming genomes to be self-contained 'programs for life'.

This can be of fundamental importance for understanding life, far beyond its relevance to cancer. That's because cooperation among genes and other cellular components, rather than gene structure itself, may provide the critical explanation of cellular behavior--even if genetic variation indubitably would be one way to affect that cooperation. In part III of this series, we'll discuss the basic ideas underlying TOFT.

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